PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale
PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale
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DOI：
10.1101/gad.1709008
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发表时间：
2008-11-01
影响因子：
10.5
通讯作者：
Lazar, Mitchell A.
中科院分区：
文献类型：
--
作者：
Lefterova, Martina I.;Zhang, Yong;Lazar, Mitchell A.
过氧化物酶体增殖体激活受体γ (PPAR γ)是一种核受体，是抗糖尿病噻唑啉二酮类药物的靶标，被认为是脂肪细胞生物学的主要调节剂。虽然它调节数百种脂肪细胞基因，但PPAR γ与内源性基因的结合很少被证实。在这里，我们利用染色质免疫沉淀（ChIP）和全基因组拼接阵列，在小鼠3T3-L1脂肪细胞中鉴定了5299个PPAR γ结合的基因组区域。在大多数位点上发现了一致的PPAR γ /RXR γ“DR-1”结合基序，而RXR α的ChIP在几乎所有测试的位点上都显示了共定位。生物信息学分析还发现，CCAAT/增强子结合蛋白（C/EBP）结合基序位于大多数PPAR γ结合位点附近，全基因组分析表明，C/EBP α结合基序位于PPAR γ结合位点的3350个位置。重要的是，大多数诱导脂肪形成的基因都是PPAR γ和C/EBP α结合的，而很少是PPAR γ特异性的。C/EBP β也在许多这些基因中发挥作用，因此C/EBP α和β与PPAR γ一起是脂肪细胞特异性基因表达的必需条件。因此，PPAR γ和C/EBP因子通过相邻结合在一个意想不到的规模上协同协调脂肪细胞生物学。
Peroxisome proliferator-activated receptor gamma(PPAR gamma), a nuclear receptor and the target of anti-diabetic thiazolinedione drugs, is known as the master regulator of adipocyte biology. Although it regulates hundreds of adipocyte genes, PPAR gamma binding to endogenous genes has rarely been demonstrated. Here, utilizing chromatin immunoprecipitation (ChIP) coupled with whole genome tiling arrays, we identified 5299 genomic regions of PPAR gamma binding in mouse 3T3-L1 adipocytes. The consensus PPAR gamma/RXR gamma "DR-1"-binding motif was found at most of the sites, and ChIP for RXR alpha showed colocalization at nearly all locations tested. Bioinformatics analysis also revealed CCAAT/enhancer-binding protein (C/EBP)-binding motifs in the vicinity of most PPAR gamma-binding sites, and genome-wide analysis of C/EBP alpha binding demonstrated that it localized to 3350 of the locations bound by PPAR gamma. Importantly, most genes induced in adipogenesis were bound by both PPAR gamma and C/EBP alpha, while very few were PPAR gamma-specific. C/EBP beta also plays a role at many of these genes, such that both C/EBP alpha and beta are required along with PPAR gamma for robust adipocyte-specific gene expression. Thus, PPAR gamma and C/EBP factors cooperatively orchestrate adipocyte biology by adjacent binding on an unanticipated scale.